The present invention relates to drug delivery devices, particularly to temporary or long-term implanted drug delivery devices, and particularly to drug delivery devices which may be associated with other devices used for medical treatment.
It is known in the art that active properties can be imparted to polymeric articles by a variety of methods. One common method is to incorporate one or more activating agents into the polymeric compound during the mixing or blending phase prior to processing or manufacturing the article. Activation is accomplished by thoroughly distributing the activating agents throughout the compounding ingredients. For example, synthetic thermoplastics, natural and synthetic rubbers and other polymeric materials have been blended with activating agents such as antibacterial, antistatic, electrically conductive and other chemically or physically active agents. The activated polymeric materials are then formed into sheets, fibers, rods or other configurations by molding, casting, extruding, calendering and/or other manufacturing or processing operations.
A second method widely used to impart certain active properties to the exposed or working surface is to apply a compound containing active agents to that surface. For example, anti-fouling marine paints, antifungal sprays and coatings, fire-resistant coatings and antistatic coatings have been applied to the surface of the article. The activity of such coating is superficially skin deep and surface activity is lost to the extent that the activated coating peels or is mechanically abraded, chipped or washed away from the inactive substrate. While this method affords certain flexibility in providing an activated surface, it is at best subject to severe limitations of available range of active ingredients that can be applied in this manner and it provides limited service life and efficiency.
Another method for the production of activated articles is to expose the article to the vapors of a volatilized chemical. This ancient technique has long been applied to textiles, polymer sheets, or the like and comprises vaporizing a volatile agent, usually a biologically active agent, and then exposing the textile or other article to the vapors. A major disadvantage of this method, however, is that it requires special buildings, ventilation and recovery equipment, and safety procedures. Since the active agent has a volatilization temperature which necessarily is much lower than the melting point of the article to which the activating vapors are applied, the activation may be readily lost where the article is exposed to elevated temperatures. Thus, the treated material may be rapidly deactivated when subjected to wet or dry heat, for example, by exposure to steam sterilization or other high temperature washing procedure, intense sunlight etc.
The use of controlled release implants for administering estradiol to ruminant animals has been described in U.S. Pat. No. 4,191,741. During implantation of such implants, conditions may be unsanitary, causing infections which could lead to loss of the implant. Use of an antibiotic or germicide layer, or a coating on the surface of the implant to reduce infections and to improve implant retention has been described in U.K. Patent No. 2 136 688 A. There an antibiotic coating facilitates parenteral administration of the implants under non-sterile conditions. Requirements for cleaning any implant needle, the site of implantation, and the implantation itself are minimized or reduced. Other infection-resistant implant materials have been described in the art, such as in U.S. Pat. No. 4,581,028 which describes infection-resistant materials suitable for use as vascular graft prostheses or other implanted devices.
It is known that antimicrobial agents can be layered or coated onto the surface of an implant to inhibit infection at the site of implantation. However, some difficulties have been encountered in implementing that technology. Surface-applied antimicrobial agents have been found to be easily dislocated from the surface of the implant by nominal mechanical activity on the implants, including during packaging. Loss of antimicrobial coating reduces the activity of the treatment significantly. Coating uniformity may also be difficult to control.
U.S. Pat. No. 3,857,934 provides a method for activating nonporous polymeric articles by applying the activating agents to one surface of the article so that the agents migrate throughout the body of the article and impart an effective level of activity throughout the article and on surfaces to which the activating agent has not been applied. The articles made by this method comprise an active layer which is applied on one surface of the article, and which contains an active migrating agent. The concentration of the agent is in excess of the concentration needed to provide an effective level of activity in the layer, and is sufficient, upon migration of the agent from the layer, to impart an effective level of activity throughout the entire article. The high concentration of the active migrating agent in the layer also provides a reservoir of activating material capable of replenishing the effective surface activity of the article.
The methods and products of U.S. Pat. 3,857,934 do not require extreme processing conditions so that volatile activating agents are conveniently used at normal temperatures; toxic agents can be handled safely; and a wide variety of inactive polymers can be given almost any desired activation. Only stocks of inactive articles are needed and the desired activation may be applied when desired. The activated article has long-lasting properties which persist even if a surface layer is removed and which are replenished from the reservoir of activating agent contained within the active layer.
U.S. Pat. No. 4,819,662 describes a device referred to as a steroid lead and a process for providing medical activity through introduced chemistry in a cardiac electrode. The invention comprises an implantable cardiac pacing lead including a porous platinum electrode, a flexible electrically conductive coil, and a crimp tube coupling the electrode to the distal end of the coil. There is a recess in the crimp tube, open to the electrode at the crimp distal tube end, which houses a matrix impregnated with a therapeutic drug. The electrode itself is highly porous and may be loaded with a therapeutic drug in liquid or solid form. The drug, because of its highly porous exposure to the environment, is immediately released upon implantation of the cardiac pacing device. A variety of different matrices carrying therapeutic drugs may be housed in the recess to provide elution of different drugs and at different rates.
U.S. Pat. No. 4,846,844 describes an improved antimicrobial implant coating comprising a silicone fluid in contact with the surface of the implant and a microbial agent in contact with the silicone fluid. The silicone fluid may be first applied to the implant and the antimicrobial agent may be applied to the fluid, for example as a dust applied to the liquid coating. The effectiveness of the application is asserted to derive from the high affinity of the silicone fluid to both the implant surface and to the antimicrobial agent.
One or more drug delivery collars or annuli may be associated with a medical device such as a catheter, fixed delivery tube, electrical element (e.g., wire or casing), fixation helix, electrode or the like to provide rated delivery of one or more drugs particularly targeted for a specific or general area of the body. The microporous collar or annulus (hereinafter, generally referred to a the drug delivery element) may be sufficiently rigid that general movement of the body or organs around the collar will not bend the drug delivery element sufficiently that the openings of the drug delivery element alter so much as to dramatically change the rate of delivery of the drug(s) during the bending action.
The drug delivery element is microporous, with open pores on its exterior and at least part way through the body of the drug delivery element so that drug may elute out of the pores into the body. The drug delivery element is microporous (rather than porous) so that the drug is delivered over an extended period of time rather than immediately released into any liquid environment into which it is placed. The size of the pores, the viscosity of the liquid (or solid fill when it is wet by the environment), the physical relationship between the drug and the walls of the pores (e.g., mutually attractive, neutrally attractive, or repulsive, such as based upon their relative hydrophilicity or hydrophobicity) will assist in determining or tailoring the rate of release of the drug into the biological system into which the drug delivery element is introduced.
The drug delivery element offers simplicity in manufacture and loading of the drug into the drug delivery element. Once the porous element has been manufactured, the various drugs may be provided to the device simply by immersing the drug delivery element into a solution, dispersion, emulsion, or suspension of the drug, allowing the drug to penetrate into the pores, and then the device is dried or maintained in a desired wet state. The collar or annulus may also provide a stiffening effect to the leading edge of a catheter or lead to facilitate its positioning or movement through a patient. Collars or annular elements may also be manufactured (during the shaping of the collar or annulus) by mixing the porous matrix forming composition with the drug to be delivered, and then shaping the collar or annulus by hardening the matrix forming material in a mold or press.